Pramipexole Enhances Reward Learning by Preserving Value Estimates
Don Chamith Halahakoon, Alexander Kaltenboeck, Marieke Martens, John G. Geddes, Catherine J. Harmer, Philip J. Cowen, Michael Browning
Abstract
Dopamine D2-like agonists show promise as treatments for depression. They are thought to act by enhancing reward learning, however the mechanisms by which they achieve this is not clear. Reinforcement-learning accounts describe three distinct candidate mechanisms; increased reward sensitivity, increased inverse decision-temperature and decreased value-decay. As these mechanisms produce equivalent effects on behaviour, arbitrating between them requires measurement of how expectations and prediction errors are altered. We characterized the effects of 2-weeks of the D2-like agonist pramipexole on reward learning and used fMRI measures of expectation and prediction error to assess which of these three mechanistic processes were responsible for the behavioral effects. 40 healthy volunteers (50% female) were randomized to 2-weeks of pramipexole (titrated to 1mg/day) or placebo in a double-blind, between-subject design. Participants completed a probabilistic instrumental-learning task before and after the pharmacological intervention, with fMRI data collected at the second visit. Asymptotic choice accuracy, and a reinforcement learning model, were used to assess reward learning. Pramipexole increased choice accuracy in the reward condition, with no effect for losses. Participants who received pramipexole had increased BOLD response in the orbital frontal cortex during the expectation of win trials but decreased BOLD response to reward prediction-errors in the ventromedial prefrontal cortex. This pattern of results indicates that pramipexole enhances choice accuracy by reducing the decay of estimated values during reward learning. The D2-like receptor agonist pramipexole enhances reward learning by preserving learned values. This is a plausible mechanism for pramipexole’s anti-depressant effect.